Asthma is a major public health problem affecting over 23 million people in the US, resulting in excess of $50 billion in healthcare expenditures per year. There is increasing evidence suggesting that in utero exposures can influence the genome resulting in increased susceptibility to asthma. In utero smoke (IUS) exposure has been associated with asthma susceptibility; however, the biologic mechanisms underlying this association have not been fully elucidated. MicroRNAs (miRNAs) are known to fine-tune the relative expression of hundreds of target genes and provide stability to gene expression regulatory networks. Animal models demonstrate that miRNAs are integral to normal in utero development, and that abnormal miRNA expression during development results in postnatal disease, suggesting that miRNAs that are modified during development by IUS exposure may be critical determinants of asthma susceptibility later in life. However, the role of miRNAs has neither been investigated in the context of IUS exposure in human lung development, nor in the developmental origin of asthma. We propose a novel integrative genomics approach incorporating miRNAs, gene expression, and DNA methylation in human subjects to investigate the role of miRNAs and their integrative networks (INs) in lung development and asthma susceptibility. Our proposal describes our plan to: identify miRNAs and the INs that are expressed, and modified by IUS exposure in developing human lung, and are also associated with asthma susceptibility and disease severity. In addition to vastly expanding our knowledge of the role miRNAs and their INs in human lung development and the signature of IUS exposure, this project will aid in the identification of pathways for novel therapeutic agents for the treatment of asthma.